Fig. 1.

GGA3 deletion increases BACE1 at similar levels in young 5XFAD and non-5XFAD mice. a-b Representative immunoblots of hippocampus (a) and cortex (b) homogenates from 4 months old GGA3WT, GGA3Het, GGA3KO, GGA3WT;5XFAD, GGA3Het;5XFAD and GGA3KO;5XFAD mice probed with anti-BACE1 (D10E5), i-APP (A8717), and anti-GAPDH (MAB374) antibodies. Levels of full-length APP are increased in GGA3WT;5XFAD mice compared to GGA3WT mice c-d Densitometry levels of BACE1 were normalized to levels of GAPDH, which was used as loading control. Levels of BACE1 were expressed as relative to BACE1 levels in homogenates from GGA3WT mice set to 1.0. Graphs represent BACE1 levels in the hippocampus (c) or cortex (d) of mice from the six different genotypes. GGA3 deletion significantly increased BACE1 levels in the hippocampus and cortex from both 5XFAD and non-5XFAD mice. However, BACE1 levels in GGA3KO and GGA3KO;5XFAD mice were similar in both hippocampus and cortex. GGA3WT;5XFAD mice had significantly higher BACE1 levels than GGA3WT mice in the hippocampus but not in the cortex. BACE1 levels were also increased in both hippocampus and cortex of GGA3Het;5XFAD mice compared to GGA3Het mice. Moreover, GGA3 haploinsufficiency increased BACE1 levels in both the hippocampus and cortex of GGA3Het;5XFAD mice compared to GGA3WT;5XFAD mice. Total number of mice in each group is indicated within bars. All graphs represent mean ± SEM. One-way ANOVA with Fisher’s LSD post hoc tests was applied to each genotype group. * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001